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Unveiling mechanisms of differentiation in neuroblastoma: from pathway discovery towards epigenetic-targeted drugs

  • Full or part time
  • Application Deadline
    Friday, May 29, 2020
  • Funded PhD Project (Students Worldwide)
    Funded PhD Project (Students Worldwide)

About This PhD Project

Project Description

Cell fate determination and differentiation are processes that are crucial in developmental biology, which assigns cells their functional roles and gives them a unique identity. It is a result of differential gene expression, epigenetic modifications, ceased proliferation, and morphological changes converting the precursor cells to specialised ones committed to a specific lineage via activation of the retinoid X/A nuclear receptors (RXR/RAR) axis [ref]. Retinoic acid receptor (RAR) and retinoid X receptor (RXR) are groups of ligand-activated transcription factors. These receptors heterodimerise to RAR/RXR to bind to retinoic-acid response element (RAREs) in the promoter of target genes. The therapeutic approach based on induced cell differentiation of transformed cells into mature phenotypes is one of the most promising strategies in new anti-neoplastic treatment. Retinoids represent the most frequently used group of differentiation inducers, both in leukaemias and in some types of solid tumours.

Neuroblastoma is a rare childhood cancer of undeveloped nerve cells, responsible for more than 1 in 10 childhood cancer deaths. Patient outcome ranges severely, from the cure in >90% of patients with the nonaggressive disease to <50% in aggressive. The shared plasticity of neuroblastoma cells and developing neural crest stem cells inspired the idea that cell differentiation might be an effective neuroblastoma therapy. The possibility that neuroblastoma cells could be differentiated into Schwann cells has not yet been studied therapeutically. RA treatment causes cell differentiation by the formation of neurite-like structures followed by neurite outgrowth and neuronal network formation in vitro. Differentiating neuroblastoma cells holds promise in inducing tumour growth arrest and treating minimal residual disease. However, evidence of potential toxicity and intrinsic or acquired resistance substantially limits the use of retinoids in clinical protocols.

This project aims to model differentiation using microphysiological multicellular models of neuroblastoma in vitro followed by identification of weaknesses in the Retinoid signalling pathway and the development of effective epigenetic targeted therapies for children with this disease.

Key references: 1. Piskareva, O, Stallings, R. (2015) Neuroblastoma. In: Epigenetic Cancer Therapy edited by Gray S., Elsevier. 2. Das S, Bryan K, Buckley PG, Piskareva O, Bray IM, Foley N, Ryan J, Lynch J, Creevey L, Fay J, Prenter S, Koster J, van Sluis P, Versteeg R, Eggert A, Schulte JH, Schramm A, Mestdagh P, Vandesompele J, Speleman F, Stallings RL. Modulation of neuroblastoma disease pathogenesis by an extensive network of epigenetically regulated microRNAs. Oncogene. 2013 Jun 13;32(24):2927-36.




Background

This Scholarship is a new prestigious award aiming to develop future biology leaders in academia and industry. This will particularly suit ambitious doctoral candidates interested in pursuing research in medicinal biology while gaining valuable training and experience in the delivery of undergraduate teaching in Foundation Year Biology.

Programme Details

Research will be carried out in the research facility in RCSI St. Stephen’s Green. The 4-year PhD Scholarships will consist of an €18,000 annual stipend (tax free), PhD student fees and a research consumables budget.


Programme Structure

The PhD (Doctor of Philosophy) degree by dissertation is the highest postgraduate award at level 10 on the National Framework of Qualifications and represents a substantial body of research work performed over 4 calendar years. The 4year full-time Biology PhD Programme includes training in the form of taught modules/workshops.

RCSI is committed to supporting an effective supervisory system for students to ensure that the successful applicants optimise their research and career potential through the programme. Clear oversight and supervision of all PhD projects will be provided by both a Principal and Subsidiary Supervisor (co-Supervisor), and all projects are reviewed annually.

In addition, the student will teach undergraduate laboratory practicals and tutorials as required under the direction of the Head of Department or nominee (to a maximum of 6 hours per week during term time).

Requirements In order to be admitted to PhD Programme, candidates must have been awarded a 2.1 grade, or above, in a relevant accredited undergraduate degree (Honours Bachelor degree or recognised equivalent NFQ level 8 degree from an accredited Higher Education Institution). If such a degree was not obtained through the medium of English language, applicants must show certified evidence of proficiency in the English language at an IETLS level of 6.5 or above.

Application Process

The application process includes ranking the projects (listed below) by the candidate. Projects will be assigned to successful candidates based on supervisor agreement and availability.

Shortlisting of applicants will be undertaken by the panel of assessors. All shortlisted candidates will be interviewed and their referees contacted directly by RCSI. An indicative timescale is given below.

Applications Open: 10 March 2020
Applications Close: 29 May 2020 (17:00 GMT)
Shortlisting: 18 June 2020
Interviews: End-June 2020 (Skype may be used)
Position begins: October 2020

How do I apply?

Download and fill in the Application Form found here:
- Only applications submitted through this form will be accepted: https://forms.office.com/Pages/ResponsePage.aspx?id=50FwYBKocEa9MDD52yEPBhzgnmH8dBtPo-wzaX6dfsdUNEwzMVhQVTZZUUswR1RISU1GMTAyNjkxRy4u
- Shortlisted candidates will be invited for interview.
- Only their referees will also be contacted at this stage for a reference.
- Interviews will be held at RCSI Dublin (123 St Stephen’s Green). Skype may be used if necessary.
- The Head of the School will offer the successful candidate a scholarship. -
- Only at this stage does the candidate go through the formal registration process using the ‘Apply Online’ system at RCSI.

Applications must include:
(i) a completed application form
(ii) English language requirements – see https://www.rcsi.com/dublin/postgraduate/policies-and-guidelines/english-language-requirements.

All documents must be:
- in PDF format
- in English
- accessible, clear and legible
- easily identifiable

Please label all files in the following format: Biology_PhD_2016_CV_JoeyBloggs.pdf. Replace "_CV" with "_letter", "_form" or "_transcript" as appropriate.

Deadline All applications must be made online by Friday 29th May 2020 (17:00 GMT).

It is the candidate’s responsibility to ensure that all documents are submitted on time. Late and/or incomplete applications will not normally be assessed. Only applications submitted through the School of Postgraduate Studies Recruitment portal will be considered. Do not send CVs directly to projects leads.

Contact details For enquiries please contact Dr Olga Piskareva at . For technical queries regarding application submission please contact Dr Anthony Chubb at .

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